KR20070024254A - Sustained-release tablets comprising cilostazol - Google Patents

Abstract

A sustained-release tablet comprising cilostazol is provided to delay the release of the cilostazol to be able to be administered one time per one day, and prevent significant increase of the cilostazol concentration in blood to reduce the side effects of the cilostazol. The matrix-type sustained-release tablet comprising cilostazol is characterized in that the release of the cilostazol is controlled by using a low-viscous hydroxypropylmethylcellulose to be administered one time per one day. The tablet comprises 15-50 wt.% of the low-viscous hydroxypropylmethylcellulose, 15-45 wt.% of the cilostazol and 5-70 wt.% of a pharmaceutically acceptable additive. The tablet further comprises a release-controlling polymer.

Description

Sustained-release tablets comprising cilostazol

FIG. 1 is a graph showing changes in blood concentration obtained by administering a cilostazol-containing matrix sustained-release tablet prepared in accordance with an embodiment of the present invention and a commercially available cilostazol rapid-release tablet (pretal tablet ™). This is a graph of blood concentration change expected when 12-hour administration of stasol immediate release.

The present invention relates to a sustained-release tablet containing cilostazol.

Cilostazol inhibits phosphodiesterase (type III) in platelets, thereby increasing antiplatelet activity by increasing cAMP in platelets, and in vascular smooth muscle, it exhibits vasodilator action. Used in patients with vascular disorders. In addition, this action is known to be useful for preventing atherosclerosis by inhibiting vascular smooth muscle cell proliferation that resides in the vascular endothelium. It is currently used to prevent ischemic symptoms such as ulcers, pain, and colds caused by chronic arterial obstruction (Berger's disease, obstructive atherosclerosis, diabetic peripheral angiopathy, etc.), and is used for reinhibition after cerebral infarction. It is also known to have ulcer and anti-inflammatory effects. Depending on age and symptoms, the dosage is appropriately increased or decreased. However, in general adults, 100 mg orally should be administered twice a day.

Existing cilostazol formulations are twice a day, which has the disadvantage of poor patient compliance, and conventional cilostazol immediate-release preparations result in a rapid rise in blood concentration when administered, such as headache, headache, tachycardia, etc. It is known to cause side effects (see Am J Cardiol 2001; 87 (suppl): 28D-33D and US Patent Publication No. 2002/0058066).

In addition, since cilostazol is poorly soluble and its absorption rate decreases toward the lower part of the small intestine, the overall bioavailability of the conventional release control formulation may be reduced. PCT Patent Publication No. WO 00/57881 discloses cilostaz in the form of fine powder. A method is disclosed for increasing the small intestinal uptake of cilostazol using a formulation in the form in which the sol is dispersed and / or dissolved in combination with a dispersing agent and / or a solubilizing agent.

Therefore, the technical problem to be achieved by the present invention is to provide a cilostazol-containing sustained-release tablet that can be administered once a day by delaying the release of cilostazol. That is, the technical problem to be achieved by the present invention is to provide a cilostazol-containing sustained-release tablet which reduces the side effect of cilostazol by delaying the release of cilostazol and preventing the blood concentration of cilostazol from rapidly increasing.

Another technical problem to be achieved by the present invention is not only to increase the solubility of cilostazol, but also to increase the total absorption rate of cilostazol by extending the gastrointestinal retention time and delaying the passage of gastrointestinal tract to reach the lower part of the small intestine. It is to provide a cilostazol-containing sustained-release tablet.

In order to achieve the above technical problem, the present invention provides a cilostazol-containing matrix sustained-release tablet in which the release of cilostazol is controlled to enable a daily administration using low-viscosity hydroxypropylmethylcellulose. (sustained-release tablet)

Preferably, the present invention provides a cilostazol-containing matrix sustained-release tablet, characterized in that the viscosity of the low-viscosity hydroxypropylmethylcellulose is 80 to 120 cP when measured at 20 ° C. with a 2% aqueous solution.

Preferably, the present invention contains 15 to 50% by weight of low viscosity hydroxypropylmethylcellulose, 15 to 45% by weight of cilostazol and 5 to 70% by weight of a pharmaceutically acceptable additive in the sustained-release tablet. A cilostazol-containing matrix sustained-release tablet characterized in that, more preferably, 25 to 45% by weight of low viscosity hydroxypropylmethylcellulose, 20 to 40% by weight of cilostazol, 1 to 8% by weight of binder, and It provides a cilostazol-containing matrix sustained-release tablet characterized in that it contains 10 to 65% by weight of a filler.

The present invention also provides a cilostazol-containing matrix comprising low viscosity hydroxypropylmethylcellulose, controlled release polymer and cilostazol, in which release of cilostazol is controlled so that it can be administered once daily. Provides a sustained-release tablet (matrix).

Preferably, the present invention is a low-viscosity hydroxypropyl methyl cellulose 10 to 25% by weight, 5 to 25% by weight of the high viscosity polymer for controlling release, cilostazol 15 to 45 in the sustained-release tablet further containing the release control polymer It provides a cilostazol-containing matrix sustained-release tablet, characterized in that it contains by weight and 5 to 70% by weight of a pharmaceutically acceptable additive, more preferably, 15 to 25% by weight, low viscosity hydroxypropylmethylcellulose, release Cilostazol-containing matrix type, characterized in that it contains 5 to 20% by weight of the control high viscosity polymer, 20 to 40% by weight of cilostazol, 1 to 8% by weight of the binder and 10 to 35% by weight of the filler Provide slow release tablets.

Hereinafter, the cilostazol-containing matrix sustained-release tablet of the present invention will be described in more detail.

According to the present invention, the preparation of cilostazol sustained-release tablet using low-viscosity hydroxypropylmethylcellulose not only slows the release of cilostazol, but also the gastric retention time and gastrointestinal tract due to the viscosity of low-viscosity hydroxypropylmethylcellulose. The increase in time can slow the time to reach the lower intestine where absorption of cilostazol is difficult, and the solubility of cilostazol can be improved due to the solubilization effect of low viscosity hydroxypropylmethylcellulose, which can help to improve the absorption rate. Based on amazing facts

Without considering the fact that cilostazol has a low absorption rate in the lower part of the small intestine, when cilostazol sustained-release tablets are prepared using a high-viscosity polymer for release control, which is a conventional method for preparing sustained-release tablets, the absorption rate of cilostazol in vivo may be lowered. have. In the cilostazol sustained-release tablet of the present invention, since the low viscosity hydroxypropylmethylcellulose and cilostazol are present evenly mixed, the water affinity of the low viscosity hydroxypropylmethylcellulose improves the solubility of the cilostazol present in the vicinity. It is expected to play a role.

In particular, since cilostazol has a considerably long half-life of 11-13 hours, it is thought that once-daily administration can be achieved by controlling the release of cilostazol from the formulation to some extent. Therefore, in the case of producing sustained-release tablets using high-viscosity polymers for release control, the content of high-viscosity polymers for release control must be reduced to meet the proper dissolution pattern. As a result, sufficient and sustained viscosity to slow the time to reach the small intestine can be obtained. Difficult to give That is, the tackiness (swelling property) of the matrix-type sustained-release tablet should be maintained while passing through the gastrointestinal tract. When the sustained-release tablet is manufactured using only a high-viscosity polymer for release control, its content is small, so it is difficult to continuously maintain the tackiness (swellability). In addition, because of the above-mentioned high viscosity polymer for the release control is low, there is a fear that the deviation of the sustained-release tablet elution pattern will be large, which means that there is a high possibility of the deviation between individuals and within individuals.

The present invention is also directed to sustained-release tablets rather than sustained-release granules for the preparation of sustained-release preparations that overcome the fact that cilostazol is poorly soluble and has low absorption in the lower intestine. It is based on the fact that tablet type sustained release formulations are advantageous for increasing the bioavailability of cilostazol in cilostazol-containing sustained release formulations since it takes more time to pass.

Accordingly, the present invention provides a cilostazol-containing matrix sustained-release tablet in which the release of cilostazol is controlled to enable a daily administration using low viscosity hydroxypropylmethylcellulose. These sustained-release tablets serve to lower the peak blood concentration (Cmax) of cilostazol, which may not only reduce side effects of cilostazol, but may also be convenient to take and significantly improve patient compliance.

However, cilostazol may be lowered in the lower part of the small intestine, so if the release is delayed too much, the bioavailability may be lowered. Therefore, the cilostazol release profile of the Korean Pharmacopoeia Dissolution Test Method 2, paddle rotation speed 75 rpm And 10-60% immediately after 2 hours, 30-90% immediately after 4 hours, and 50-100% immediately after 6 hours when tested under the condition of 900 ml of an elution medium 0.5w / w% sodium lauryl sulfate aqueous solution. It is preferable to adjust to.

The hydroxypropyl methyl cellulose of the present invention has a relatively high content in order to sufficiently maintain the swellability (adhesiveness) of the matrix sustained-release tablet during the passage of the gastrointestinal tract, so it has a low viscosity of less than 200 cP when measured at 20 ° C. with a 2% aqueous solution. It is more preferable that the viscosity is 80-120 cP.

Typically, controlled release of a drug is achieved by adding a release-controlling polymer, but the same formulation is not commonly applied to all drugs, but the physical properties of the drug (eg, solubility) and excipients (binders) added together with the drug. It is well known to those skilled in the art that the present invention may exhibit different emission patterns depending on the filler, lubricant, lubricant, etc.), the manufacturing method, and the like. In particular, since the cilostazol-containing matrix sustained-release tablet of the present invention must simultaneously control the fact that the cilostazol is absorbed in the lower part of the small intestine as well as sustained release, it can be said that it is difficult to design a formulation with conventional sustained release information.

Preferably, the present invention is characterized in that it contains 15 to 50% by weight of low viscosity hydroxypropylmethylcellulose, 15 to 45% by weight of cilostazol and 5 to 70% by weight of pharmaceutically acceptable additives relative to the total weight of the sustained-release tablet. Provided is a stasol-containing matrix sustained-release tablet, more preferably, the present invention is 25 to 45% by weight of low viscosity hydroxypropylmethylcellulose, 20 to 40% by weight of cilostazol, 1 to 8% by weight binder It provides a cilostazol-containing matrix sustained-release tablet characterized in that it contains% and 10 to 65% by weight filler.

Even in tablets with the same components, the release rate varies depending on the content of the drug. In the case of slow-release tablets, the content of one component is different because the content of one component changes as a result. Has a great effect on the release rate of the drug. In particular, in the cilostazol-containing sustained-release tablet of the present invention, the low-viscosity hydroxypropylmethyl cellulose is very important to be used in the above-mentioned content range because it performs not only a sustained release role but also a tackifying and solubilizing role. More specifically, when less than 15% by weight of low-viscosity hydroxypropylmethylcellulose is used relative to the total weight of the sustained-release tablet, it is difficult to achieve the purpose of sustained release, solubilization and tackiness (maintenance of swelling). There is a fear that the release will be too slow and the total absorption will decrease.

The present invention also includes low viscosity hydroxypropylmethylcellulose, controlled release polymer and cilostazol, in which release of cilostazol is controlled to be administered once daily within the scope of not impairing the object of the present invention. A cilostazol-containing matrix sustained-release tablet is provided.

It is desirable to control the release of cilostazol using only low-viscosity hydroxypropyl cellulose, but may further contain a release-controlling polymer in order to more precisely control the release pattern of cilostazol or optionally to adjust the tablet size. Can be.

The release controlling polymer of the present invention is methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrroly Don, polyvinylacetate, polyalkene oxide, polyalkeneglycol, polyethylene-polypropylene polymer, polyoxyethylene-polyoxypropylene polymer, diethylaminoacetate, aminoalkyl methacrylate copolymer, glyceryl behenate, carrageenan ), Alginic acid, sodium alginate, chitosan, gelatin and gum (Gum) any one or more selected from the group may be used, but is not limited thereto.

When the release controlling polymer is used, preferably, the present invention is 10 to 25% by weight of low viscosity hydroxypropylmethylcellulose relative to the total weight of the sustained-release tablet, 5 to 25% by weight of the high viscosity polymer for controlling release, 15 to 45% by weight of cilostazol and pharmaceuticals It provides a cilostazol-containing matrix sustained-release tablet characterized in that it contains 5 to 70% by weight of additives, and more preferably, 15 to 25% by weight of low viscosity hydroxypropylmethylcellulose relative to the total weight of the sustained-release tablet , Containing 5 to 20% by weight of a high viscosity polymer for controlling release, 20 to 40% by weight of cilostazol, 1 to 8% by weight of binder and 10 to 35% by weight of filler It provides a matrix sustained-release tablet.

As a pharmaceutically acceptable additive included in the cilostazol-containing sustained-release tablet of the present invention, a binder, a filler, a disintegrator, a lubricant, and the like may be used, but the present invention is not limited thereto. It may be used as long as it is pharmaceutically acceptable without departing from the object of the present invention. The binder may be corn starch, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, etc., but other components used to control the cilostazol release pattern in the present invention. Polyvinylpyrrolidone is preferable in consideration of the harmony with. As the filler, microcrystalline cellulose, pregelatinized starch, lactose or a mixture thereof may be used.

Methods for producing a matrix type sustained-release tablet using viscous polymers are well known to those skilled in the art. However, in terms of solubilization of cilostazol, low viscosity hydroxypropyl methyl cellulose and cilostazol are preferably mixed finely, so cilostazol and low viscosity hydroxypropyl methyl cellulose using a solvent rather than a general dry method and a direct method. The wet granulation method of manufacturing and granulating a granule containing therein is more preferable.

Hereinafter, the following examples and the like will be described in order to describe the present invention in more detail. However, embodiments according to the present invention can be modified in many different forms and the scope of the present invention should not be construed as being limited to the embodiments described below. Embodiments of the present invention are provided by way of example in order to facilitate a specific understanding of the present invention.

<Examples 1-6> Preparation of sustained-release tablet of matrix type

To prepare a sustained-release tablet of the matrix type with the components and contents shown in Table 1 below, the viscosity of the hydroxypropyl methyl cellulose shown in Table 1 means the viscosity measured at 20 ℃ in a 2% aqueous solution. First, povidone K30 (binder) was dissolved in ethanol to prepare a binder solution. After cilostazol, microcrystalline cellulose (excipient), hydroxypropylmethylcellulose (release control polymer) and a part of the pregelatinized starch (excipient) (50%) were mixed well, granules were prepared by using the binder solution. The granules were dried in a drying oven (40 ° C.) until the loss on drying was about 2.5% and established in a 30 mesh sieve. Then, the wells and the remaining ingredients were mixed well and tableted to a tablet weight described below with a tableting machine (KI-1300, Kisan Machinery, South Korea).

number Ingredient Name (Unit: mg) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 One Cilostazol 200 200 200 200 200 200 2 Microcrystalline cellulose 100 100 100 100 50 50 3 Hydroxypropylmethylcellulose (100 cps) 75 75 50 150 100 200 4 Hydroxypropylmethylcellulose (4,000 cps) - 25 50 - - - 5 Povidone K30 16.5 24 24 26.5 19 24 6 Pregelatinized starch 120 120 120 120 120 120 7 Colloidal Silicon Oxide 12 12 12 12 12 12 8 Stearic acid 16.5 16.5 16.5 16.5 16.5 16.5 9 Ethanol (μl) 110 160 160 160 127 160 1 tablet (mg) 540 572.5 572.5 625 517.5 622.5

<Experimental Example 1> Cilostazol Dissolution Evaluation

The samples prepared in Examples 1 to 6 were subjected to the dissolution test according to the method of the pharmacopeia elution test method 2 (paddle method) (paddle rotational speed 75 rpm). As a dissolution medium, 900 ml of 0.5w / w% sodium lauryl sulfate aqueous solution was used, and as a control, dissolution test was performed by simultaneously adding two tablets of Pretal Tablet (100 mg) ™ (Otsuka Pharmaceutical, Korea). All six samples were tested and their average values are shown in Table 2. The amount of cilostazol eluted in the dissolution medium relative to the initial content contained in one tablet was expressed as a percentage (%).

Hour (hr) Control Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 0.5 97.0 10.7 11.7 11.4 9.9 10.7 8.3 One 99.2 20.3 24.1 23.7 20.9 20.8 12.6 1.5 99.8 32.0 31.0 33.7 27.6 26.8 18.6 2 - 47.4 48.1 47.8 42.0 40.5 24.9 3 - 68.2 62.8 60.4 57.7 55.9 37.1 4 - 82.5 82.1 79.7 76.9 75.7 49.9 6 - 95.8 94.9 95.1 92.4 91.2 71.4 8 - 98.1 99.2 99.4 98.3 99.1 83.4 10 - - - - - - 92.3

As shown in Table 2, it can be seen that the sustained-release tablet of the present invention gradually releases cilostazol. It can be seen from the dissolution test results of Examples 4 to 6 that the release of cilostazol is delayed when the content of hydroxypropylmethylcellulose (100 cP), which is a release controlling polymer, is increased. As can be seen from the dissolution test results of Examples 2, 3 and 5, it can be seen that the cilostazol is released to a certain extent irrespective of the viscosity of the release controlling polymer.

In addition, it can be seen that the standard deviation of the cilostazol dissolution test of the sustained-release tablet of the present invention prepared in Example 6 is very small at 0.78, 1.51, 1.83, 1.65, 2.91, 3.14, 2.60, 2.08 and 0.72 at each time period. This, in turn, may help to reduce the absorption deviations between individuals and / or within the sustained-release tablet.

On the other hand, as a result of measuring the swelling of the sustained-release tablet prepared in Examples 1 to 6 during the dissolution test time, all the examples maintained the swelling outside the matrix throughout the dissolution test time, the cilostazol sustained-release tablet prepared in Example 6 The swelling state was the best.

Experimental Example 2 Evaluation of Mucoadhesion

The small intestine of the rat (weight 350 ~ 450g, 12 weeks old) was separated and washed several times with physiological saline. Thereafter, the separated small intestine was cut to a length of 10 cm, vertically dissected, fixed to the plastic plate with the small intestine mucosa upwards, and washed again with 100 ml of saline. The test sample (sustained-release tablet containing cilostazol of Examples 1, 3, 5, and 6) is evenly placed on the mucosa of the small intestine and the small intestine tissue to which the test sample is attached is placed in a desiccator (93% relative humidity, room temperature). It was left for minutes. Then, remove the plastic plate attached to the small intestine tissue and place it obliquely at an inclination of about 30 degrees, wash the tissue with saline flowing down at a flow rate of 20ml / min using a peristaltic pump for 5 minutes and then attached the test sample Was observed. The degree of adhesion of the test sample was measured according to the following criteria, and the results are shown in Table 4.

Dimension

Good: Test sample adheres well to tissue (no movement of tablets)

Moderate: The test sample is usually attached to the tissue (the tablet moves more than 2 cm from the initial attachment position)

Poor: The test sample is not attached to the tissue and falls off (the tablet moves more than 5 cm from the initial attachment position)

Adhesion Example 1 usually Example 3 Good Example 5 Good Example 6 Good

Experimental Example 3 Evaluation of Blood Concentration Change

The absorption pattern of cilostazol-containing sustained-release tablet according to the present invention was evaluated. Serum concentrations were measured by allowing healthy adult males (average age 30 years, n = 4) to take the cilostazol-containing combination prepared in Example 6. In order to compare the cilostazol immediate release and the absorption pattern, the change in blood concentration was also measured by taking a single dose of commercial tablet ™ 100 mg (n = 3).

The cilostazol blood concentration was measured by Chromatographic Analysis of Cilostazol in Human Plasma (Park Young-Joon et al., Korean Academy of Pharmaceutical Sciences: Was measured by application. Specifically, cilostazol blood concentration was used by semi-microbore HPLC equipped with an automated column switching system. Plasma deproteinized with methanol was injected and passed through a Capcell Pak MF Ph-1 column, followed by protein removal. The cilostazol fraction was transferred to an intermediate C18 column (column switching A >> B, mobile phase in 10% aqueous acetonitrile solution). The cilostazol fraction concentrated on the intermediate C18 column was allowed to be separated and analyzed on a semi-microbore C18 column (column switching B >> A, mobile phase 40% acetonitrile).

The results are summarized in Table 4 and FIG. 1. As shown in Figure 1, the cilostazol-containing sustained-release tablet of the present invention is lower than the cilostazol immediate-release preparation has a lower maximum blood concentration (Cmax) is thought to reduce side effects, slowing the loss rate is found to be sustained in vivo Can be. As shown in FIG. 1, although the AUC (area under the blood concentration curve) of the cilostazol-containing sustained-release tablet according to the present invention corresponds to about twice the AUC of the rapid release of cilostazol, the cilostazol was sustained. It can be seen that the water absorption does not drop.

Hours (hr) Example 6 Total Tablet ™ Blood concentration (ppm) Standard Deviation Blood concentration (ppm) Standard Deviation 0.5 0.03 0.01 0.28 0.17 One 0.12 0.11 0.38 0.17 2 0.31 0.13 0.68 0.32 3 0.38 0.09 0.84 0.24 4 0.42 0.10 0.76 0.17 5 0.42 0.09 0.50 0.22 6 0.45 0.14 0.40 0.29 7 0.44 0.16 0.31 0.29 8 0.46 0.15 0.24 0.24 10 0.50 0.15 0.11 0.09 12 0.51 0.27 0.07 0.02 24 0.28 0.17 0.03 0.01

The present invention provides a cilostazol-containing sustained-release tablet that can be administered once daily by delaying the release of cilostazol. The cilostazol-containing matrix sustained-release tablet of the present invention can reduce the number of daily doses to improve patient compliance, as well as lower the peak blood concentration of cilostazol, thereby lowering the incidence of side effects of cilostazol. In addition, the cilostazol-containing matrix sustained-release tablet of the present invention can reduce the total absorption rate of cilostazol in cilostazol sustained-release tablet by delaying gastric retention time and gastrointestinal transit time and improving the solubility of cilostazol.

Claims (9)

A cilostazol-containing matrix sustained-release tablet in which release of cilostazol is controlled to allow daily administration using low viscosity hydroxypropylmethylcellulose. The cilostazol-containing matrix sustained-release tablet according to claim 1, wherein the viscosity of the low-viscosity hydroxypropylmethylcellulose is 80 to 120 cP when measured at 20 ° C. with a 2% aqueous solution. The method of claim 1, wherein the sustained-release tablet contains 15 to 50% by weight of low viscosity hydroxypropylmethylcellulose, 15 to 45% by weight cilostazol and 5 to 70% by weight of a pharmaceutically acceptable additive relative to the total weight of the sustained-release tablet Cilostazol-containing matrix sustained-release tablet which is used. According to claim 1, wherein the sustained-release tablet is 25 to 45% by weight of low-viscosity hydroxypropylmethylcellulose, 20 to 40% by weight of cilostazol, 1 to 8% by weight of the binder (filler) and the filler (10) A cilostazol-containing matrix sustained-release tablet containing 65% by weight. The cilostazol-containing matrix sustained-release tablet according to claim 1, wherein the sustained-release tablet further contains a release controlling polymer. The method of claim 5, wherein the release control polymer is methyl cellulose, ethyl cellulose, hydroxy methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, poly Vinylpyrrolidone, polyvinylacetate, polyalkene oxide, polyalkeneglycol, polyethylene-polypropylene polymer, polyoxyethylene-polyoxypropylene polymer, diethylaminoacetate, aminoalkyl methacrylate copolymer, glyceryl behenate, Cilostazol-containing matrix sustained-release tablet, characterized in that any one or more selected from the group consisting of carrageenan, alginic acid, sodium alginate, chitosan, gelatin, and gum. According to claim 5, wherein the sustained-release tablet is a low viscosity hydroxypropyl methyl cellulose 10 to 25% by weight relative to the total weight of the sustained-release tablet, 5 to 25% by weight of the high-viscosity polymer for controlling release, 15 to 45% by weight cilostazol and pharmaceutically acceptable additives Cilostazol-containing matrix sustained-release tablet containing 5 to 70% by weight. According to claim 5, wherein the sustained-release tablet is 15 to 25% by weight of the low viscosity hydroxypropyl methyl cellulose relative to the total weight of the sustained-release tablet, 5 to 20% by weight of the high-viscosity polymer for release control, 20 to 40% by weight of cilostazole, 1 to 1 binder A cilostazol-containing matrix sustained-release tablet containing 8% by weight and 10 to 35% by weight of a filler. According to claim 4 or 8, wherein the binder is polyvinylpyrrolidone and the filler is any one or more selected from the group consisting of microcrystalline cellulose, pre-gelatinized starch and lactose Sol-containing matrix sustained-release tablet.

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